There are about 30,000 cystic fibrosis (CF) patients in the US and another 1,000 individuals are diagnosed annually. The intestinal tract is one of the major organs affected in CF and despite vigorous therapy, malnutrition is common in this disease. Poor nutrition is a strong predictor of mortality in CF patients, whose proximate cause is airway failure due to excessive destructive lung inflammation. The long term research goal is to understand intestinal dysfunction in CF in order to identify new therapeutic directions that improve quality of life and longevity. The objective of this application is to determine the extent to which impaired intestinal function contributes to the excessive immune response in the CF lung. The central hypothesis of this project is that impaired intestinal innate defenses in CF, including decreased alkaline phosphatase (IAP) activity, compromised gut barrier function, and small intestinal bacterial overgrowth, contribute to the excessive immune activity of the lung, which is characteristic of this disease. IAP is part of the innate defenses and is important to intestinal barrier function. Also, lipopolysaccharide (LPS or endotoxin) is a natural substrate of IAP. After dephosphorylation by IAP, LPS is detoxified. Bacterial overgrowth of the CF small intestine is common, which will increase the amount of endotoxin available to enter the circulation. Thus, it is proposed that due to IAP deficiency, increased gut permeability, and intestinal bacterial overgrowth, more bioactive endotoxin from the gut can enter the circulation and reach distant sites like the airways. Gut-derived circulating endotoxin will exacerbate inflammation in the CF lung when infection occurs. A mouse with a targeted disruption of the gene responsible for CF (Cftr knockout mouse) will be used. The CF mouse has several changes in the small intestine that make it an excellent model for human CF disease. The CF mouse also has significantly elevated airway immune activity. Two Specific Aims are proposed for this project: (1) Determine the extent to which the mucosal barrier function of the intestine is impaired in the CF mouse;and (2) Determine the extent to which treatments that ameliorate the CF intestinal phenotype also improve barrier function and decrease airway immune activity in the CF mouse. RELEVANCE: The fatal genetic disease cystic fibrosis (CF) affects about 30,000 people in the US and 1,000 more are diagnosed annually. Poor functioning of the gastrointestinal system is an important factor in the decline in respiratory function which is the eventual cause of death in CF. Successful completion of the proposed project is expected to lead to new therapeutic approaches to improve intestinal function, quality of life, and longevity of CF patients.